29

Injectable Fillers: Review of Material and

Properties
Natalie Huang Attenello, MD2 Corey S. Maas, MD, FACS1,2

1 Department of Facial Plastic and Reconstructive Surgery, University Address for correspondence Corey S. Maas, The Maas Clinic, 2400 Clay
of California, San Francisco, California Street, San Francisco, CA 94115 (e-mail: drmaas@maasclinic.com).
2 Department of Aesthetic and Facial Plastic Surgery, The Maas Clinic,
San Francisco, California

Facial Plast Surg 2015;31:29–34.

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Abstract With an increasing understanding of the aging process and the rapidly growing interest
in minimally invasive treatments, injectable facial fillers have changed the perspective
for the treatment and rejuvenation of the aging face. Other than autologous fat and
certain preformed implants, the collagen family products were the only Food and Drug
Administration approved soft tissue fillers. But the overwhelming interest in soft tissue
Keywords fillers had led to the increase in research and development of other products including
► soft tissue fillers bioengineered nonpermanent implants and permanent alloplastic implants. As multiple
► hyaluronic acid injectable soft tissue fillers and biostimulators are continuously becoming available, it is
► calcium important to understand the biophysical properties inherent in each, as these constitute
hydroxylapatite the clinical characteristics of the product. This article will review the materials and
► poly-L-lactic acid properties of the currently available soft tissue fillers: hyaluronic acid, calcium
► polymethyl- hydroxylapatite, poly-L-lactic acid, polymethylmethacrylate, and autologous fat (and
methacrylate aspirated tissue including stem cells).

Minimally invasive procedures have revolutionized the Historical Background

treatment paradigm for facial rejuvenation and may very
well be one of the most significant changes in the recent
history for facial plastic surgery. Initially utilized for the
treatment of fine lines and wrinkles, the concept of fillers
has expanded to include correction of volume loss and
augmentation of the aging face. Since bovine collagen was
introduced as the first injectable filler in the early 1970s,
several other products have been developed for soft tissue
augmentation ranging from both synthetic materials to
autologous tissue. The ideal soft tissue filler is one that is
effective, nonimmunogenic, nontoxic, noncarcinogenic,
nonmigratory, easily applied, nonpalpable, painless, and
long lasting.1 Currently available injectable fillers can be
broadly classified into the following three different catego-
ries: hyaluronic acid (HA) derivatives, synthetic fillers, and
autologous fat. This article reviews the varying properties
and materials inherent in the currently available injectable
fillers (►Table 1).
The utility of facial fillers traces back to the 19th century
when autologous fat was first described as a soft tissue filler
for cosmetic deformity by the German physician, Dr. Franz
Neuber.2 This was later replaced by paraffin in the early 1900s
but was soon abandoned after reports of embolization,
granuloma formation, and migration.3 In the mid-20th cen-
tury, a shift was seen toward purified synthetic polymers in
the form of injectable silicone. Although seemingly promising
at first, the Food and Drug Administration (FDA) eventually
banned this for similar complications of granuloma forma-
tion.4 Although, microdroplet injection of limited amounts of
silicone material is still used today as an off-label use for
silicone that is FDA approved for ocular injections.5–7 Teflon, a
synthetic polytetrafluoroethylene polymer, was next tested
as a soft tissue filler, but it was quickly abandoned because of
the inflammatory reaction and injection difficulty that was
experienced.8 Until the early 1980s, none of the previously

Issue Theme Management of Facial Copyright © 2015 by Thieme Medical DOI http://dx.doi.org/
Volume; Guest Editors, Edward D. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0035-1544924.
Buckingham, MD, and Mark Glasgold, MD New York, NY 10001, USA. ISSN 0736-6825.
Tel: +1(212) 584-4662.
30 Injectable Fillers Attenello, Maas

Table 1 Comparison of soft tissue fillers

Filler Manufacturer Composition Needle size Depth

Hyaluronic acid Restylane Galderma, Ft. 20 mg/mL hyaluronic 29–30 gauge Mid-to-deep dermis
Worth, TX acid; 400 µm particle
size
Perlane Galderma, Ft. 20 mg/mL hyaluronic 27–29 gauge Deep dermis,
Worth, TX acid; 750–1,000 µm superficial subcutis
particle size
Juvéderm XC Allergan, Inc, 24 mg/mL with 0.3% 27 gauge Mid-to-deep dermis
Irvine, CA lidocaine
Juvéderm Voluma Allergan, Inc, 20 mg/mL with 0.3% 27 gauge Deep (subcutane-
Irvine, CA lidocaine ous,
supraperiosteal)

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Belotero Merz North America, 22.5 mg/mL 30 gauge Mid-to-deep dermis
Greensboro, NC
Synthetic fillers Radiesse BioForm Medical, San 30% calcium hydroxyl- 25–27 gauge Subdermal
Mateo, CA apatite microspheres/
70% carrier gel
Sculptra Dermik Laboratories, 367.5 mg powder of 26 gauge Deep dermis
Berwyn, PA poly-L-lactic acid
microspheres
ArteFill Suneva Medical, San 20% polymethylme- 26 gauge Dermal–subdermal
Diego, CA thacrylate suspended junction
in 80% solution with
3.5% bovine collagen
and 0.3% lidocaine
Autologous fat Autologous fat Autologous Liposuctioned fat 18 gauge nee- Subcutaneous
dle with blunt
cannula

attempted facial fillers had received FDA approval until the
bovine collagen, Zyderm (Inamed Corp., Santa Barbara, CA)
was approved in 1981. The approval of Zyderm led to
widespread research and development of other fillers includ-
ing alloplastic and implantable materials as well as the
renewed interest and utilization of autologous fat.9 Even
with an increase in research, though, bovine collagen was
the only FDA approved filler for the next two decades until
2003 when the FDA approved the first HA dermal filler
(Restylane; Galderma, Ft. Worth, TX). Since this approval,
the last decade has seen a dramatic increase in the number of
FDA approved facial fillers in response to the growing popu-
larity of minimally invasive facial rejuvenation procedures.
Over 2 million soft tissue filler procedures were performed in
the United States in 2012.10
Hyaluronic Acid Derivatives
HA is a naturally occurring glycosaminoglycans composed of
D-glucuronic acid and N-acetyl-D-glucosamine found in the
dermis. At physiologic pH, HA has excellent biocompatibility
as it is anionic and thus binds to water extensively where 1 g
HA can bind up to 6 L water.11 Because of this intrinsic
solubility, although, it is rapidly cleared when injected into
the normal skin—a characteristic that should be carefully
controlled if utilized as a dermal filler.11–14 Therefore, chemi-
cal modification to the carboxyl acid group, and cross-linking
with dialdehydes and disulfides, was necessary to change its
mechanical properties—such as gel firmness and half-life of
the HA product (►Figs. 1 and 2).11,15 The different composi-
tions of the chemically modified HA fillers are at the discre-
tion of the manufacturer and thus create variations amongst
the HA products as fillers.
The concentration of HA in the filler differs with each
manufacturer and is typically listed as the total amount of HA
(soluble and insoluble HA, mg/mL) found in the filler.12 It is
important to understand that only the cross-linked HA, or the
more insoluble HA, functions as the dermal filler by resisting
degradation and providing more longevity in the dermis. The
listed soluble-free HA, or unmodified HA, are usually by-
products of their chemical modifications and will quickly be
metabolized given their solubility.
Most HAs are viscoelastic and this is measured with the
complex modulus, which is the sum of the elastic modulus
(G′) with the viscous modulus (G″). The elastic modulus (G′) is
used most commonly to characterize the firmness of the gel
and measures the resistance of a material to deformation—the
stiffer the material then the higher the G′.12,16 This is deter-
mined by the degree and strength of interaction in the cross-
linking HA as well as the HA concentration. Clinically, this
becomes important because gels with a higher G′ will have
better resistance to the dynamic forces incurred with facial
muscle movement providing long lasting support and volu-
mization, this is ideal for areas such as the nasolabial folds and
marionette lines.12 One should be cognizant, although, that
gels with a higher G′ can cause visible small blue papules or

Facial Plastic Surgery Vol. 31 No. 1/2015


Fig. 1 Cross-linking schematic of hyaluronic acid. (Courtesy of Galderma, Ft. Worth, TX.)
nodules (Tyndall effect) if injected superficially in the
skin.17,18 In contrast, in areas that are more static or with
superficial wrinkles, resistance to deformation by muscle
movement is less critical and gels with lower G′ are better
utilized. These gels are also better suited for areas that need
more softness, such as the lips.12 Although all HA gels vary in
elastic modulus, even the ones with the highest G′ are much
softer than the elastic modulus of human dermis, which has
G′ in the 3-MPa range.12,19
Swelling varies among products and manufacturers and
can partially be attributed to the molecular characteristic of
HA—the concentration, amount of cross-linking, and the
products used to hydrate the gel.12 A gel that is fully hydrated
will not swell any further upon injection into the dermis as
they have already reached their hydration capacity. Converse-
ly, nonequilibrium gels have a tendency to swell after injec-
tion and thus one must consider underfilling when using
these types of gels.12
Fig. 2 Cross-linking of hyaluronic acid. (Courtesy of Galderma,
Ft. Worth, TX.)
Injectable Fillers Attenello, Maas 31
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The particle size and the range of distribution of particle
size are another important component for the composition of
HA gels as this will influence the extrusion force needed for
injection. A larger gel particle will be more difficult to inject
through a small bore needle and a more narrow range of
distribution of particle size can decrease interruptions in the
flow of particle extrusion, as uniformity is ideal to provide
better control of gel placement.12 The G′ also affects the ability
to inject the product through a small bore needle as firm gels
with a higher resistance to deformation must be sized as a
smaller particle and have a narrow particle size range to
facilitate particle extrusion. Whereas softer gels with a low
G′ can have a broader range of particle size because these gels
can be easily deformed as they pass through the needle.12
A unique characteristic of HA is its reversibility via enzy-
matic digestion with injection of hyaluronidase.20 This natu-
rally occurring enzyme is FDA approved as a temporary drug
dispersion agent by cleaving HA between C1 of an N-acetyl-
glucosamine moiety and C4 of a glucuronic acid moiety.21
Thus, its function as a reversal agent for HA is actually off-
label, but it has been utilized commonly for reversal of HA
fillers. Because of the varying biochemical compositions of
the different HA products, it should be noted that each
product may respond differently to hyaluronidase.21
Distributed by the same manufacturer, both Restylane and
Perlane (Galderma, Ft. Worth, TX) have similar qualities and
are considered biphasic gels because they consist of particles
suspended in a liquid (►Table 1). These HA molecules are
cross-linked with 1,4-butanediol diglycidyl ether, which will
decrease the rate of degradation as well as increase the
surface area of the molecule.11 Restylane is a non–animal-
stabilized HA filler introduced in 1996 derived from the
fermentation of Streptococcus species and has 20 mg/mL of
HA with the average particle size of 400 µm.11 Perlane is
similar to Restylane but has a larger particle size (range, 750–
1,000 µm) and a decrease in surface area and thus contains
less gel beads, 8,000 gel beads/mm, compared with Restylane
Facial Plastic Surgery Vol. 31 No. 1/2015
32 Injectable Fillers Attenello, Maas
which contains 100,000 gel beads/mm.11,22 Theoretically, this
can decrease its rate of degradation and increase its duration
of effect.11 Because Perlane has a larger particle size, it is
better suited for deeper levels of injection such treatment for
deep cutaneous depressions. Perlane also needs to be injected
through a 27-gauge needle compared with a 30-gauge needle
used for Restylane, which may cause slightly more pain upon
injection.11,23 Restylane, in contrast, can be injected superfi-
cially given its smaller particle size, although like all HA fillers,
Restylane does create Tyndall effect in standard concentra-
tions when used in the papillary dermis.11,17 Overall, both
Restylane and Perlane have a higher G′, hence are more firm
with less spreading of product and is therefore better suited
for placement in the subdermal level, particularly in the
midface.20 In a real-time ultrasound study, Micheels et al
demonstrated that Restylane, with its high viscosity and least
tendency to spread, was distributed fairly evenly in well-
defined boluses within the deep reticular dermis.20,24
Juvéderm (Allergan Inc, Irvine, CA) is currently available in
two types: Juvéderm XC and Juvéderm Voluma with a HA
concentration of 24 and 20 mg/mL, respectively (►Table 1).
Unlike Restylane and Perlane, the Juvéderm products do not
get passed through sizing screens via sieves and instead are
not quantified by their particle size, but are considered
“cohesive molecules” of cross-linked HA.20,25 Thus, manufac-
tured using the proprietary Hylacross technology, Juvéderm
products are considered a monophasic gel. Both of the
Juvéderm products have an intermediate G′ and viscosity,
which leads to a higher likelihood of spreading after implan-
tation and a softer feel.20 Because Juvéderm XC has a lower G′
and viscosity than Juvéderm Voluma, it is ideal for areas
where palpability is less desirable, and a small amount of
product spreading may be beneficial, such as the lips.20,26 In
addition, because Juvéderm XC is less dense, it is optimal for
medium-depth wrinkle correction, such as forehead wrin-
kles, glabellar lines, nasolabial folds, and moderate nasal
furrows.11 Juvéderm Voluma, FDA approved in October 2013,
was biochemically modified to be the first and only product
for correction of volume loss in the midface. By combining a
low-molecular-weight (< 1 mDa) and high-molecular-weight
(> 1 mDa) HA, this created an increase in covalent bonding to
the cross-linking agent which increased the G′.27 Combined
with a higher G′ and a low-swelling capacity, this made
Juvéderm Voluma ideal for long-term deep soft tissue volume
restoration, potentially lasting up to 2 years.27
Belotero (Merz North America, Greensboro, NC) was FDA
approved in 2011 for treatment of moderate-to-severe
nasolabial folds and wrinkles.28 Belotero has a higher con-
centration of non–cross-linked HA and is considered poly-
densified as the cross-linking is not uniform throughout.29
This results in a low viscosity and the lowest G′ of the
currently available HA fillers.28 With these properties, Belo-
tero is utilized mainly in areas for superficial injection in the
dermis or subdermal plane as it is a softer product (due to the
low G′) that allows it to spread more evenly given its low
viscosity.29 In a histologic evaluation, Flynn et al observed
Belotero diffuse into the dermis (except the papillary dermis)
evenly and widely.30 Clinically, Belotero is useful for very fine
Facial Plastic Surgery Vol. 31 No. 1/2015
lines such as the forehead, vermillion border, and in the tear
trough.29
Synthetic Fillers
Radiesse
Radiesse (Merz North America, Greensboro, NC) is a synthet-
ic, semisolid filler composed of 30% calcium hydroxylapatite
and 70% carrier gel that was initially approved in 2006 for the
treatment of facial wrinkles and folds as well as HIV-associ-
ated facial atrophy and then later approved in 2009 for more
cosmetic applications. It is considered a long-lasting, non-
permanent filler that is highly biocompatible given that it is
identical to the physiologic mineral component found in
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human bone and teeth.23 Because of this, Radiesse has no
antigenicity and thus provokes a little immune response.
The calcium hydroxylapatite (CaHA) microspheres are
suspended in the carrier gel composed of sodium carboxy-
methylcellulose, water, and glycerin mix and this allows the
particles to be easily delivered upon injection. Each CaHA
particle size is between 25 and 45 µm, and therefore should
be injected with a 25- to 27-gauge needle (►Table 1). After
injection, the carrier gel that fills the interstitial space even-
tually dissipates and is replaced with soft tissue growth with
the CaHA acting as a scaffold.31,32
Because Radiesse is mostly injected subdermally near or
well below the dermal-subcutaneous junction, it is not a true
filler.32 On injection, it provides a 1:1 level of correction, so
over injection is not required. Injection too superficially can
lead to visibility of the white material and nodularity and too
deep of placement may require more material for adequate
correction.33 Because of its opaque color, CaHA is less ideal for
areas such as the lips as opposed to certain HAs, which are
translucent. In a study comparing the rheologics of the differ-
ent soft tissue fillers, Radiesse was in the high-viscosity and
high-elasticity (G′) group and Radiesse with 0.3% lidocaine was
in the medium group.34 These properties can be translated into
clinical advantages and disadvantages. Studies have supported
this notion as shown on a split-face study that less Radiesse
(a very high viscosity and high elasticity filler) was required for
nasolabial fold correction than a soft tissue filler with a lower
viscosity and elasticity.35,36 The addition of lidocaine to CaHA
modestly dilutes the elasticity and viscosity of the product,
which can be advantageous in certain clinical situations, such
that the extrusion force is reduced and CaHA is easier to spread
and less palpable but still providing adequate lift.34
Sculptra
Polylactic acids were originally synthesized by French chem-
ists in 1954 from the α-hydroxy-acid family and have been
used safely as suture materials, resorbable plates, and screws
in orthopedic, neurologic, and craniofacial surgery.37 Ap-
proved by the FDA in 2004 for soft tissue restoration in
lipoatrophy in HIV patients, this was later expanded to
include cosmetic applications in 2009 as Sculptra (Dermik
Laboratories, Berwyn, PA). Sculptra functions as more than
just a soft tissue filler, but as a biostimulator by stimulating
the production and vascularization of collagen.38,39 Studies

have demonstrated an increase in skin thickness because of
collagen formation as early as 6 weeks after injection, which
remained for up to 96 weeks.38,40 Sculptra comes as a powder
of poly-L-lactic acid microspheres mixed with sodium
carboxymethylcellulose mannitol, and sterile water for injec-
tion. The microspheres range from 1 to 63 µm in diameter that
eventually gets dissolved into carbon dioxide and water.
Initial studies showed a high rate of nodule formation,
especially in patients with severe soft tissue or lipoatrophy,
although these nodules resolved spontaneously and was
attributed to product placement too superficially or in the
perioral and periocular region.4,41
Sculptra was approved in treatment of shallow to deep
nasolabial folds, facial wrinkles and lines, and improvement of
contour deficiencies with placement recommended subcutane-
ously.4 Because results rely on new collagen formation after
several weeks, it will not have instantaneous results and thus can
be used in conjunction with other fillers such as HA or CaHA.38
ArteFill
ArteFill (Suneva Medical, San Diego, CA) is a third generation
polymethylmethacrylate (PMMA) and collagen filler that was
first developed over 20 years ago in Germany as Arteplast and
its second generation successor, Artecoll. Although both fillers
had adequate soft tissue filler capabilities, they also had an
unacceptable rate of granuloma formation and were not
approved by the FDA. Further research elucidated that
PMMA microsphere size was critical to avoid phagocytosis
by macrophages and giant cell formation resulting in inflam-
mation. Associated observations suggested that small PMMA
microspheres, less than 20 µm in diameter, provoked a foreign
body response.42,43 Addressing these observations, the syn-
thetic formulation was changed and ArteFill consisted of 20%
PMMA microspheres, 30 to 50 µm in diameter, which is
suspended in 80% of mostly denatured bovine collagen. Be-
cause of the bovine collagen, a skin test is needed because of a
3% prevalence of hypersensitivity.38,44 With a dramatic de-
crease in granuloma formation from 2.5% with Arteplast to less
than 0.01% with ArteFill and a better safety profile, ArteFill was
approved for treatment of the nasolabial folds in 2006.45
ArteFill is also a collagen production stimulator.42 Because
ArteFill has a smooth, round surface and is suspended in
collagen, it allows tissue ingrowth into the interstitial space
around the microspheres. This decreases the displacement of
the filler, which also increases the volume. The resultant
increase in volume is 20% PMMA and 80% autologous connec-
tive tissue.38,45 Because the microspheres are too big for
degradation by phagocytosis, they are permanent micro-
spheres and cannot be reversed. Given the irreversibility
and the risk of nodularity around the lip and eyes, ArteFill
is not recommended for these areas.
Autologous Fat Injection
Autologous fat has many characteristics of an ideal filler—it is
biocompatible, inexpensive, readily available, easily acquired,
and noncarcinogenic; but the long-term results of lipotrans-
fer are still variable and unpredictable.46 The first autologous
fat transfer was performed by Dr. Franz Neuber in 1893 to fill
Injectable Fillers Attenello, Maas 33
scars on the forearm. In the early 1900s, others saw some
improvement in facial contour after the placement of fat,
though the results were overall considered unreliable.23,46,47
In 1950, Peer reported an average loss of 45% in the weight of
the free fat implant by 1 year and this emphasized the
importance of a well-vascularized recipient site.48 It was
not until the 1970s, at the advent of liposuction, that renewed
interest in autologous fat for micro-lipoinjection became
popular as a means for esthetic correction of facial volume
loss.23,49 In addition, autologous fat spurred interest into
other autologous donor material, and it should be noted
that platelet-rich plasma has been utilized via a proprietary
system and injected into the dermis showing promising
results when used for the nasolabial folds, acne scars, or
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superficial rhytids.50,51
Adipose tissue is composed of adipocytes contained within
a matrix of connective tissue and a small vascular pedicle that
supplies each fat cell, also known as “lipid lobule.”46 There
have been studies proposing mesenchymal adult stem cells
that may differentiate into adipocytes, though this warrants
further research.52
A blunt-tipped microcannula is used to harvest fat from
various regions of the body, which then gets purified from the
serosanguinous debris.23 The harvested fat is then prepared
for facial injection and overcorrection by 30 to 50% is recom-
mended given the amount of resorption. A biopsy of an
injected tissue showed fibrotic tissue as a result of an inflam-
matory reaction as possible mechanism for facial volume
restoration.23 Fat injection may be used to address multiple
areas including the nasolabial and melolabial folds, lips, and
hemifacial atrophy.
Conclusion
The development of facial fillers is a constantly advancing field
with the goal of refining products to maximize the efficacy
while minimizing the adverse effects. With the ability to
manipulate the biochemical compositions of the inherent
characteristics of the fillers, it is becoming apparent that no
singular filler can treat the entire face. Instead, different fillers
are emerging as unique products best suited for certain regions
given the varying characteristics and esthetic needs of the face.
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